Recent Advances in Multidrug-Resistant TB of HIV/TB coinfection.2013
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clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
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Faculty and Disclosure Information
Richard E. Chaisson, MDProfessor of Medicine, Epidemiology and International Health Johns Hopkins UniversityDirector, Johns Hopkins Center for AIDS Research and Center for Tuberculosis ResearchBaltimore, Maryland
Richard E. Chaisson, MD, has disclosed that his spouse has ownership interest in Merck.
Maunank Shah, MD, has no significant financial relationships to disclose.
Maunank Shah, MDAssistant ProfessorDepartment of Infectious DiseaseJohns Hopkins UniversityMedical DirectorTuberculosis ProgramBaltimore City Health DepartmentBaltimore, Maryland
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Tuberculosis Drug Resistance: Definitions
Acquired drug resistance
– Selection of resistant mutants by inadequate treatment
Primary drug resistance
– Disease caused by an organism that was resistant when infection was acquired
Multidrug-resistant TB
– Resistance to at least isoniazid and rifampin (and other rifamycins)
Extensively drug–resistant TB
– MDR-TB plus resistance to fluoroquinolones and an injectable agent (amikacin, kanamycin, capreomycin)
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Drug-Resistant TB: MDR and XDR
Drug-resistant TB first arises from improper treatment
– Wrong selection of drugs by doctors or poor adherence to treatment by patients results in selection of naturally occurring mutants with innate resistance
Patients with acquired drug-resistant TB can spread infection to others, causing primary resistance in their contacts
In many countries, transmission of drug-resistant TB is now more common than acquired resistance[1]
The key prevention strategies for drug-resistant TB are:
– Avoid creating new cases by treating TB properly and thoroughly
– Prevent transmission of infection through early and proper diagnosis and infection control
1. WHO. 2013. Surveillance of drug resistance in tuberculosis.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
MDR-TB: Epidemiology
In 2012, an estimated 450,000 new cases of MDR-TB emerged globally[1]
Among all new cases of TB, 3.6% are estimated to have MDR-TB[1]
An estimated 20% of persons with previously treated TB have MDR-TB[1,2]
More than one half of the new MDR-TB cases occur in China, India, and the Russian Federation[1]
Mortality in MDR-TB patients usually exceeds 10%[3]
In 2012, MDR-TB caused an estimated 170,000 deaths[1]
1. WHO. 2013. Update on MDR-TB. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12. 3. Wells CD. Curr Infect Dis Rep. 2010;12:192-197.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
MDR-TB Among New TB Cases, 1994-2012
WHO. 2013. Surveillance of drug resistance in tuberculosis.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
MDR-TB Among Previously Treated TB Cases, 1994-2013
WHO. 2013. Surveillance of drug resistance in tuberculosis.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Diagnosis of MDR-TB
Gold-standard test: Culture of patient specimen (sputum) to assess inhibition of M tuberculosis growth in the presence of antibiotics (phenotypic assay)
Solid-media assays: Result may not be available for 3-6 wks
Automated liquid culture systems: Faster and more sensitive than solid-media cultures; results available in 1-2 wks
Rapid molecular tests can identify genotypic resistance in 1-2 days
– Xpert TB/RIF identifies M tuberculosis and rifampin resistance using cartridge-based real-time PCR
– Line-probe assays (eg, Hain GenoType) identify genotypic resistance to both isoniazid and rifampin
1-2 days 1-2 wks 3-6 wks 4-12 wks
Average Turnaround Time for Diagnostic Tests
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
WHO Recommendations: Diagnosis of MDR-TB Xpert MTB/RIF should be used as the initial diagnostic test in
individuals suspected of MDR-TB[1]
However, Xpert MTB/RIF does not eliminate need for conventional microscopy, culture, and DST to monitor treatment progress and to detect resistance to drugs other than rifampin [1]
1. WHO. Xpert MTB/RIF system policy statement 2011. 2. Aurum Institute. Managing TB in a new era of diagnostics. 2012.
Xpert Result[2]
Xpert Positive,Rifampin
Susceptible
Xpert Positive, Rifampin Resistant
Xpert Positive, Rifampin
Unsuccessful
Xpert Negative Xpert Unsuccessful
Interpretation Drug-sensitive TB Presumed MDR-TB Presumed drug-sensitive TB
TB unlikely but further investigation
necessary
No diagnosis
Actions Treat for drug-sensitive TB;
collect sputum for microscopy and culture with DST
Treat with regimen for MDR-TB; collect
sputum for TB culture/DST
Treat for drug-sensitive TB;
collect sputum for microscopy and culture with DST
Collect sputum for TB microscopy and
culture to exclude TB
Collect sputum for TB
microscopy and culture to
exclude TB
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Performance of Xpert MTB/RIF vs Other Diagnostic Modalities
Boehme C, et al. Lancet. 2011;377:1495-1505.
Proportion of TB Cases and Resistance Results by Each Method in Culture-Positive Patients
Liquid cultureMTB/RIF testSolid cultureMicroscopy
TB
Ca
ses
De
tect
ed (
%)
100
90
80
70
60
50
40
30
20
10
01000 20 40 60 80
Days to Detection
100%
90%
89%
67%
Line-probe assayMTB/RIF testPhenotypic drug-susceptibility testing
0 20 40 60 80 100 120 140Days to Detection
100%
94%
RIF
Res
ista
nce
Det
ecte
d (
%)
100
90
80
70
60
50
40
30
20
10
0
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Time to DST Results Halved With MDR Line Probe Assay in South Africa
Time Period Median Time, Days (IQR) P Value
Before LPA After LPA
1 Sputum collection to lab receipt of sample
1 (0-1) 0 (0-1) < .001
2 Lab receipt to DST testing 27 (21-34) 19 (12-31) < .001
Smear positive 26 (21-43) 13 (9-16) < .001
Smear negative 29 (22-43) 29 (22-42) .497
3 DST testing 9 (2-14) 0 (0-1) < .001
Total Sputum collection to DST results available
52 (41-77) 26 (11-52) .008
Sputum collection
Lab receiptof sputum
DST started DST results reported
1 2 3
Hanrahan CF, et al. PLoS One. 2012;7:e49898.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Time to MDR Treatment Before and After Line-Probe Assay in South AfricaFrom initial patient sputum sample to date of appropriate MDR therapy
Mos to MDR Treatment
80 2 4 6
1.00
0.75
0.50
0.25
0Cu
mu
lati
ve P
rop
ort
ion
on
M
DR
Tre
atm
ent
After LPABefore LPA (study data)Before LPA (undetected MDR modeled)
Hanrahan CF, et al. PLoS One. 2012;7:e49898.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Resistance at Start of Second-line TB Therapy
Drug Resistance, n (%)
First-line drugs Ethambutol 826 (64.6) Streptomycin 881 (69.0) 4 first-line drugs* 625 (49.0)
Second-line drugs
Any second-line drug 559 (43.7) At least 1 fluoroquinolone 165 (12.9)
Second-line Injectable drugs
Kanamycin 237 (18.5) Amikacin 205 (16.0) Capreomycin 152 (12.0) At least 1 255 (20.0) All 134 (10.5)
Other oral second-line drug
Ethionamide 249 (19.5) Aminosalicylic acid 137 (10.7) At least 1 346 (27.1)
XDR-TB 86 (6.7)
PETTS Study: Prevalence of Drug Resistance in 1278 Pts With MDR-TB 1278 pts enrolled in several
countries at start of second-line TB treatment, 2005-2008
DST done centrally at CDC
High levels of resistance to second-line drugs detected
– 43.7% with resistance to ≥ 1 second-line drug
– 20% with resistance to ≥ 1 injectable second-line drug
– 12.9% with resistance to ≥ 1 fluoroquinolone
– 6.7% with XDR-TB
Dalton T, et al. Lancet. 2012;380:1406-1417. *Isoniazid, rifampin, ethambutol, streptomycin.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
MDR-TB General Principles
An individualized approach should be undertaken
– Guided by drug susceptibility testing when available
– Assessment of comorbidities that may affect therapy should be undertaken before therapy
Never add a single drug to a failing regimen
Use at least 3-5 previously unused drugs to which an isolate has in vitro susceptibility
Supervise treatment to ensure adherence
Continue treatment for at least 18-24 mos after culture conversion
WHO. Guidelines for programmatic management of drug-resistant TB. 2011.Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Drugs for MDR-TB
Group 1: First-line oral drugsEthambutol Pyrazinamide High-dose isoniazid
Group 2: Fluoroquinolones
LevofloxacinMoxifloxacin GatifloxacinOfloxacin
Group 3: Injectable drugs
Kanamycin Amikacin CapreomycinStreptomycin
Group 4: Oral bacteriostatic second-line drugs
Ethionamide Prothionamide Cycloserine/terizidone Para-aminosalicylic acid
Group 5: Drugs of unclear efficacy
Clofazimine Clarithromycin Amoxicillin-clavulanate Linezolid Thiacetazone Meropenem-clavulanateThioridazine*Other newer drugs
Adapted from: Chang KC, et al. Respirology. 2013;18:8-21.*Newer drugs will be discussed later in the educational activity.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Building a Treatment Regimen for MDR-TB
Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians. Chang KC, et al. Respirology. 2013;18:8-21.
Step 1: Include any first-line drugs to which the isolate is susceptible
Injectables
Kanamycin Amikacin Capreomycin Streptomycin
Step 2: Add a fluoroquinolone
Fluoroquinolone
LevofloxacinMoxifloxacin Gatifloxacin
First-line Drugs
Ethambutol Pyrazinamide
Step 3: Include an injectable agent
Oral Second-line Drugs
Ethionamide Prothionamide Cycloserine/terizidone Para-aminosalicylic acid
Third-line Drugs
Clofazimine Clarithromycin Amoxicillin-clavulanate Linezolid Thiacetazone Meropenem-clavulanateThioridazineOther new drugs
Step 4: Include second-line drugs until you have 4-6 drugs to which the isolate is susceptible
Consider third-line drugs if there are not 4-6 drugs to which the isolate is susceptible
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Treatment Regimens for MDR-TB
Resistance Pattern Regimen Comments
INH and RIF Strept PZA + EMB + FQN + injectable (for ≥ 6 mos) + second-line agent if
extensive disease
Treat 18-24 mos following conversion
INH, RIF + (PZA or EMB)
(PZA or EMB) + FQN + 2 second-line agents + injectable agent (for
first 6 mos)
Treat 18-24 mos following conversion;
consider additional agents, high-dose INH
INH, RIF, PZA, EMB FQN + 3 second-line agents + injectable drug for first 6-12 mos
Treat 18-24 mos following conversion
INH, RIF, PZA, EMB, FQN
Injectable + 3 second-line agents + third-line agents
Treat 24 mos following conversion;consider high-dose INH,
Surgery
INH, RIF, PZA, EMB,injectables
FQN + all available second-line agents; consider any third-line
agents if susceptible
Treat 24 mos following conversion;consider surgery
Adapted from: Curry International Tuberculosis Center. Drug-resistant tuberculosis: a survival guide for clinicians.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
“Bangladesh” Regimen: Experimental Short-Course Treatment for MDR-TB
Controlled trial under way to confirm the efficacy of this regimen
van Deun A, et al. Am J Respir Crit Care Med. 2010;182:684-692.
*Resistance likely for many MDR patients.
Phase Drugs
4-mo intensive phase High-dose INH*Prothionamide*KanamycinGatifloxacinEthambutol*Pyrazinamide*Clofazimine
5-mo continuation phase Gatifloxacin Ethambutol*Pyrazinamide*Clofazimine
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Potency and Tolerability of Existing TB Drugs
Dorman SE, et al. Nat Med. 2007;13:295-298.
Increasing potency, reliability, reproducibility of susceptibility testing
Decreasing tolerability
Fir
st-l
ine
Dru
gs
Sec
on
d-l
ine
Dru
gs
RifampinIsoniazidPyrazinamideEthambutol
Fluoroquinolones(moxifloxacin, gatifloxacin,levofloxacin)
Injectable agentsAminoglycosides (streptomycin,amikacin, kanamycin)Polypeptides (capreomycin)
Oral bacteriostatic agents(ethionamide, protionamide, cycloserine/terizidone, p-aminosalicylic acid, thiacetazone)
Agents with unclear efficacy (clofazimine, amoxicillin-clavulanate, clarithromycin, linezolid)
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Adverse Effects of MDR-TB Drugs
Drug Toxicities and Adverse Effects
Ethambutol Visual acuity, color vision
Pyrazinamide Hepatotoxicity
Isoniazid Neurologic effects, hepatotoxicity
Injectables Vestibular, renal toxicity, hearing loss
Fluoroquinolones GI, CNS, cardiac toxicities, tendinopathy
Cycloserine/terizidone CNS toxicity, behavioral changes
Ethionamide GI toxicity, hypothyroidism
PAS GI toxicity, hypothyroidism, osteoarticular pain.
Clofazimine Changes in skin and ocular pigmentation, GI effects
Linezolid Thrombocytopenia, neutropenia, neuropathy, metallic taste
Aurum Institute. Managing TB in a new era of diagnostics. 2012.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Bedaquiline
Oral diarylquinoline
Target: ATP synthase
– Activity specific to mycobacteria
Bactericidal activity comparable to RIF-INH-PZA in mice
Sterilizing activity comparable to rifampin in mice
Synergy with PZA
No cross-resistance with other antimycobacterial drugs (INH, RIF, EMB, PZA, streptomycin, amikacin, or moxifloxacin)
Andreas K, et al. Science. 2005;307:223-227. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
Br
N O
(S)
HO(R) N
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C208: Phase II Trial of Bedaquiline for MDR-TB Stage I study: 47 pts with newly
diagnosed pulmonary MDR-TB randomized to bedaquiline or placebo in combination with 5-drug second-line TB regimen
– BDQ dose: 400 mg QD for 2 wks, then 200 mg TIW for 6 wks
BL resistance: pyrazinamide, 65%; ethambutol, 59%; kanamycin, 8%; ofloxacin, 8%; ethionamide, 8%
BDQ reduced time to culture conversion (HR: 11.8; 95% CI: 2.3-61.3; P = .003)
Incidence of AEs similar between arms
– Nausea more frequent in BDQ vs placebo: 26% vs 4% (P = .04).Diacon AH, et al. N Engl J Med. 2009;360:2397.
0
0.2
0.4
0.6
0.8
1.0
0 7 42 C
ult
ure
-Po
siti
ve P
atie
nts
(%
)14 21 28 35 49 56
Placebo (n = 24)Bedaquiline (n = 23)
Days
52%
91%
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
C208: Phase II Trial of Bedaquiline for MDR-TB Stage II study: 15 sites in Brazil,
India, Latvia, Peru, Philippines, Russia, South Africa, Thailand
Pts randomized to receive BDQ (n = 67) vs placebo (n = 66) for 24 wks with 5-drug BR
– BDQ dose: 400 mg QD for 2 wks, then 200 mg TIW for 22 wks
After Wk 24, both groups continued the 5-drug BR to total of 96 wks
Culture conversion at Wk 24 significantly higher with bedaquiline vs placebo
Cure rate also significantly higher
WHO. The use of BDQ in treatment of MDR-TB—interim policy guidance. 2013.
Outcome BDQ Placebo P Value
Median time to sputum conversion, days (95% CI)
83(56-97)
125(98-168)
< .0001
Pts with culture conversion, %Wk 24Wk 72Wk 120
78.871.262.1
57.656.143.9
.008
.069
.035
Proportion cured, %
57.6 31.8 .003
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
FDA Bedaquiline Indication
Approved by FDA in 2012 as part of combination therapy in adults with pulmonary MDR-TB
– Should be used only when an effective treatment regimen cannot otherwise be provided[1]
Recommended dose: 400 mg PO QD for 2 wks, then 200 mg PO TIW, for a total duration of 24 wks
First drug with novel mechanism approved by FDA for TB since 1971
Bedaquiline [package insert].
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
CDC Provisional Guidance on Bedaquiline
BDQ may be used as a component of TB therapy when an effective treatment regimen cannot otherwise be provided
– Administer by DOT for 24 wks with food in adults with laboratory-confirmed pulmonary MDR-TB
– Use on case-by-case basis in children, HIV-positive pts, pregnant women, pts with extrapulmonary MDR-TB, and pts with comorbid conditions on concomitant medications
– Use on case-by-case basis for durations > 24 wks
CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
WHO Interim Guidance on Use of Bedaquiline BDQ may be added to a WHO-recommended regimen in
adult MDR-TB patients under following conditions:
– When an effective treatment regimen containing 4 second-line drugs in addition to PZA, according to WHO recommendations, cannot be designed
– When there is documented resistance to any fluoroquinolone in addition to MDR
– Recommended for adults older than 18 yrs of age under carefully monitored conditions
WHO. Bedaquiline for MDR-TB. 2013.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Bedaquiline Safety Concerns
Black box warning: increase in all-cause mortality and prolongation of QT interval—monitor EKGs[1]
– 30 deaths occurred in the clinical trial program in patients receiving BDQ vs 6 on placebo[2]
BDQ should be used with caution with other drugs that can cause QT interval prolongation and EKGs should be monitored more often[1]
– Includes clofazimine and fluoroquinolones
BDQ should not be used with rifampin or rifapentine, which are strong inducers of CYP3A4[1]
1. Bedaquiline [package insert]. 2. CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Bedaquiline Monitoring
All patients should be monitored wkly for adverse effects
EKGs should be monitored at baseline and at least 2, 12, and 24 wks after starting treatment
Serum potassium, calcium, and magnesium should be measured at baseline and whenever clinically indicated, especially if QT interval prolongation is detected
All patients started should be included in a registry for ongoing monitoring
Additional notes:
– Bedaquiline should never be used as a single drug
– Bedaquiline has a long terminal half-life of 4-5 mos; should be discontinued before other drugs in regimen
– Rifamycins and other CYP3A4 inducers reduce bedaquiline concentrations
– Bioavailability is significantly affected by food
CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Delamanid (OPC-67683)
Nitro-dihydro-imidazooxazole
Derivative of metronidazole
Inhibits mycolic acid synthesis
Potent preclinical in vitro and in vivo activity against both drug-susceptible and drug-resistant strains of TB
Skripconoka V, et al. Eur Respir J. 2013;41:1393-1400.
N
O
O
FF
FOOO
ON+
N
N
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Delamanid: Phase II Trial vs Placebo
Multinational trial of pts with pulmonary MDR-TB
Pts randomized to 2 mos of
– Delamanid 100 mg (n = 161)
– Delamanid 200 mg (n = 160)
– Placebo (n = 160)
– Each with WHO BR
Primary endpoint: sputum culture conversion at 2 mos
Delamanid significantly increased rate of sputum conversion vs placebo after 2 mos of treatment
QT prolongation reported significantly more frequently with delamanid
All other AEs mild to moderate and similar among groups
Gler MT, et al. N Engl J Med. 2012;366:2151-2163.
Pat
ien
ts (
%)
41.929.6
45.4
100
80
60
40
20
0Delamanid
200 mgDelamanid
100 mgPlacebo
57/136 37/12564/141
P = .04
P = .008
n/N =
Mycobacterial Growth Indicator Tube Culture Conversion at Day 57
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
EMEA Delamanid Recommendation
In November 2013, the European Committee for Medicinal Products for Human Use recommended granting a conditional marketing authorization for delamanid for the treatment of MDR-TB
Recommended indication:
– Use as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability
EMEA. Marketing authorization for delamanid. November 2013.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Linezolid
Oxazolidinone, approved to treatdrug-resistant, Gram-positive bacteria
Good activity against MDR-TB in vitro and in animal studies
Use in TB often limited due to long-term toxicities (bone marrow suppression, neuropathy)
However, retrospective chart review (2003-2007) of 30 pts (29 with pulmonary TB) who received linezolid 600 mg QD (plus vitamin B6) as part of a regimen for MDR-TB concluded[1]:
– Culture conversion occurred in all pulmonary cases at median of 7 wks
– AEs occurred in only 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea
– Only 3 patients stopped linezolid treatment because of AEs
1. Schecter GF, et al. Clin Infect Dis. 2010;50:49-55.
F
ON
N
O
O O
NH
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Linezolid 600 mg QD immediately*
Linezolid 600 mg QDdelayed by 2 mos*
Pts with sputum-culture–positive XDR-
TB (no response to any TB drugs in previous 6 mos)
(N = 41)
Smear conversion or 4 mos
*All pts remained on background regimen of drugs they were taking before study entry.Second randomization continued at least 18 mos after smear conversion or after 4 mos on first regimen.
Linezolid 600 mg QD
22 mos
Linezolid 300 mg QD
Lee M, et al. N Engl J Med 2012;367:1508-1518.
Phase II Trial of Linezolid in Patients With XDR-TB Phase II trial in South Korea
Primary endpoint: time to sputum-culture conversion on solid medium (data censored 4 mos after study entry)
Linezolid 600 mg QD
Linezolid 300 mg QD
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Phase II Trial of Linezolid in Patients With XDR-TB Culture conversion at 4 mos:
– 79% (15/19) in immediate arm vs 35% (7/20) in delayed arm (P = .001)
87% (34/39) with negative sputum culture within 6 mos
31 pts (82%) with clinically significant AEs related to LZD
– 3 pts d/c therapy
Pts on LZD 300 mg on second randomization had fewer AEs
13 pts completed therapy without relapse
4 pts acquired LZD resistanceLee M, et al. N Engl J Med. 2012;367:1508-1518.
1.0
0.8
0.6
0.4
0.2
00 30 60 90 120 150 180
Days Since Start of LZDC
um
ula
tive
Pro
bab
ility
o
f C
on
vers
ion
Conversion Probability According to Time on Treatment
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Sutezolid (PNU-100480)
Oxazolidinone, related to linezolid
MOA: protein synthesis inhibition[1]
Like LZD, has a high barrier to resistance
More potent than LZD in mice, whole blood culture
Efficacy in mice similar to isoniazid and/or rifampin and may be synergistic with other first-line drugs
May be safer than LZD
SN
F
O
N OOH
NH
CH3
1. Alffenaar JW, et al. Antimicrob Agents Chemother. 2011;55:1287-1289.
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Early Bactericidal Activity of Sutezolid in HIV+/- Pts With Drug-Susceptible TB Significant log CFU reductions with
both sutezolid regimens during the 14-day treatment period
– 600 mg BID: -0.09 log/day (90% CI: -0.06 to -0.11)
– 1200 mg QD: -0.07 log/day (90% CI: -0.04 to -0.09)
– Trend toward superior response with BID dosing
Both dosing schedules generally safe and relatively well tolerated
– 7/50 sutezolid-treated pts experienced ALT increases to 2-3 x ULN, which were asymptomatic and resolved spontaneously
Wallis RS, et al. AIDS 2012. Abstract THLBB02. Graphic used with permission.
0
-1
-2
-3
140 2 4 6 8 10 12
Day
Ch
ang
e in
lo
g C
FU
1200 QD600 BIDHREZ
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
PA-824
PA-824: nitroimidazole-oxazine
– Active in vitro and in mouse models
Cross-resistant with delamanid
High protein binding may render PA-824 less accessible in cavities of pulmonary TB
May be useful in combination regimens; synergistic with other drugs
F
F F
O
O
O
O
ONN+
clinicaloptions.com/hivRecent Advances in Multidrug-Resistant TB
Novel Drug Combinations With PA-824 Show Promise in Mouse Models PA-824 with moxifloxacin and
pyrazinamide cures TB more rapidly than the first-line regimen in mice[1]
Bedaquiline + PA-824 + sutezolid may provide a novel 3-drug backbone for a universally active short-course regimen[2]
Regimen (Duration)
Mice Cured, % (n/N)
4 Mos 5 Mos 6 Mos
RIF-INH-PZA (2 mos) + RIF-INH (4 mos)
50(10/20)
100 (20/20)
100 (20/20)
RIF-MXF-PZA (2 mos) + RIF-MXF (3 mos)
95 (19/20)
100 (20/20)
100 (20/20)
Pa-MXF-PZA (2 mos) + Pa-MXF (4 mos)
100 (20/20)
100 (20/20)
100 (20/20)
RegimenRelapse, % (n/N) After Tx for
2 Mos 3 Mos 4 Mos
RIF + PZA + INH
ND100
(15/15)64
(9/14)
BDQ + SUT + CFZ + Pa
93 (14/15)
13 (2/15)
7 (1/15)
BDQ + SUT + CFZ
87 (13/15)
27 (4/15)
7(1/14)
BDQ + SUT + Pa
100(15/15)
43(6/14)
0(0/15)
BDQ + CFZ + Pa
100(15/15)
60(9/15)
33(5/15)
SUT + CFZ + Pa
100(15/15)
100(15/15)
100(15/15)
1. Nuermberger EL, et al. Antimicrob Agents Chemother. 2008;52:1522-1524. 2. Williams K, et al. Antimicrob Agents Chemother. 2012;56:3114-3120.
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HIV-negative or HIV-positive pts* with
newly diagnosed pulmonary smear and culture-positive drug-
sensitive TB(N = 83)
Day 14
Early Bactericidal Activity of Novel Combinations of TB Drugs Phase II trial in TB-infected pts
Diacon AH, et al. Lancet. 2012;380:986-993.
Bedaquiline + Pyrazinamide (n = 15)
Bedaquiline + PA-824 (n = 15)
PA-824 + Pyrazinamide (n = 15)
Rifampin/Isoniazid/Ethambutol/Pyrazinamide (n = 8)
Bedaquiline(n = 15)
PA-824 + Pyrazinamide + Moxifloxacin (n = 15)
*6 HIV-positive subjects.
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Early Bactericidal Activity of Novel TB Regimens
0.5
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.00 142 4 6 8 10 12
Day
Lo
g C
FU
Ch
ang
e F
rom
Bas
elin
e
BedaquilineBedaquiline + PZABedaquiline + PA-824
RHEZPA-824 + PZAPA-824 + PZA + moxifloxacin
Diacon AH, et al. Lancet. 2012;380:986-993.
Standard-of-care regimen
Novel PA-824/ PZA/moxifloxacin regimen
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Prevention of MDR-TB
Prevention of MDR-TB involves adequate, proper treatment of initial disease to prevent selection of resistance
– Prompt diagnosis with adequate TB treatment under DOT
– Rapid identification of MDR-TB and use of appropriate second-line regimens
– Avoid further evolution of resistance
– Airborne infection control
– Preventive treatment of TB/HIV coinfection with optimal use of ART
Management strategies for established cases mainly rely on specific alternative treatment regimens complemented with surgery in carefully selected cases
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Preventive Therapy in Contacts of Pts With MDR-TB in Micronesia 232 contacts of 5 pts with 2 different MDR-TB strains
105 with positive TST received preventive therapy
Strain A: resistant to isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin
– Contacts offered fluoroquinolone alone or in combination with ethionamide
Strain B: resistant to isoniazid, rifampin, and ethionamide
– Contacts offered fluoroquinolone with ethambutol
No cases of MDR-TB developed in those treated
– 28 untreated contacts developed MDR-TB
ECDC. Management of contacts of MDR TB and XDR TB patients. 2012.
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Conclusions
Current approaches to MDR-TB therapy are long, with much toxicity
Bedaquiline is the first drug with a novel mechanism of action to be approved by FDA for MDR-TB since 1971
Delamanid recently approved by European Medicines Agency
– Both agents indicated only when an effective regimen cannot otherwise be provided
Multiple new drugs are in the pipeline
Successful eradication of MDR-TB will require new drug regimens with novel drug combinations
Go Online for More CCO Educational Content on Multidrug-
Resistant TB!Interactive Virtual Presentation featuring streaming narration of these slides by expert faculty Richard E. Chaisson, MD, and Maunank Shah, MD
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